Efficacy and Initial Safety Profile of CXCL12 Treatment in a Rodent Model of Urinary Sphincter Deficiency

Abstract

Disappointing results of skeletal muscle precursor cell (skMPC) therapy for women with intrinsic urinary sphincter deficiency (ISD) associated urinary incontinence has increased interest in alternative sphincter regenerative approaches. This study was to measure the safety and efficacy of the cell homing chemokine CXCL12 versus skMPCs in a rat model of ISD. Thirty‐six adult female Sprague Dawley rats were divided into 6 treatment (Tx) conditions: (a) no ISD/noTx [Control]; (b) ISD/noTx; (c) ISD + skMPCs; (d) ISD + 3.5 mg CXCL12; (e) ISD + 7mg CXCL12; and (f) ISD + 14 mg CXCL12. Tx's were injected directly into the sphincter complex 30 days post ISD and rats euthanized 30 days post Tx. Blood samples for measurements of kidney and liver function, white and red blood cell counts, were taken at baseline and at euthanasia. Leak point pressures (LPP) were measured prior to, and sphincter collagen/muscle content measured after, euthanasia. There were no effects of treatments on white or red/white blood cell counts, kidney/liver function tests or histopathology of the urinary sphincter complex or surrounding tissues. ISD lowered LPP 35% and sphincter muscle content by 17% versus control rats. CXCL12, but not skMPC injections, restored both LPP to control values in a dose‐dependent fashion. Both skMPCs and CXCL12 restored sphincter muscle content to control values. This chemokine approach may represent a novel therapeutic option for ISD and appears, at least short‐term, to produce little clinical or tissue pathology. Stem Cells Translational Medicine 2017;6:1740–1746

The use of autologous skeletal muscle progenitor cells for adjunctive treatment of presumptive urethral sphincter mechanism incompetence in female dogs

“…As has been reported in other species, our results indicate that the urethral submucosal injection of skMPC can be used as an adjuvant treatment to achieve continence in dogs. 18,19,[24][25][26] Dogs in our study had already failed standard treatment for USMI but achieved continence rates equal to or exceeding what would have been expected of standard medical treatment in the population of dogs at large with USMI. Standard medical management for USMI is most commonly administration of an alpha-agonist (e.g., PPA), or an estrogen (e.g., diethylstilbesterol [DES] or estriol) or a combination of the 2 agents.…”

Chemokine Therapy in Cats With Experimental Renal Fibrosis and in a Kidney Disease Pilot Study

“…Through a receptor (CXCR4) mechanism, CXCL12 has a major role in cell trafficking and homing of progenitor cells to sites of injury and in enhancing cell survival once at the injury site. There are numerous reports of this regenerative capacity in various tissues (28,30,(33)(34)(35)(36)(37). We have previously used CXCL12 as a local treatment to stimulate regeneration of urogenital tissues (34,36,37).…”

“…There are numerous reports of this regenerative capacity in various tissues ( 28 , 30 , 33 – 37 ). We have previously used CXCL12 as a local treatment to stimulate regeneration of urogenital tissues ( 34 , 36 , 37 ).…”

“…The recombinant human form is commercially available and inexpensive. Injection of recombinant human CXCL12 protein has been shown to reduce fibrosis in rodent models of chronic kidney disease ( 28 ), uterine fibrosis ( 30 ), stress urinary incontinence ( 33 , 34 ), and non-human primate models of intrinsic sphincter deficiency ( 35 , 36 ) and erectile and urinary dysfunction post-radical prostatectomy ( 37 ), but its effects on collagen content and collagen fiber histomorphometry have not been tested in cat models of chronic renal fibrosis.…”

Cell Technologies in the Stress Urinary Incontinence Correction

“…The data that the cell therapy effectiveness in patients with stress urinary incontinence is lower than expected have emerged recently [ 10 , 18 , 25 , 26 , 27 ]. The main limitations of the MSC using are associated with loss of function after expansion ex vivo, poor engraftment in vivo or survival after transplantation, deposition in the injection site, as well as a lack of understanding of the exact mechanisms of action underlying therapeutic results and MSC behavior in vivo [ 13 ].…”